The hypnotics most frequently prescribed for the treatment of sleep disorders are classic benzodiazepines as well as compounds like zolpidem and zopiclone. These compounds shorten sleep latency and increase total sleep time. The pharmacological effect of these compounds is assumed to be due to a modulation of the GABA.sub.A receptor (.gamma.-aminobutyric-acid.sub.A receptor); however they neither increase neuronal release of GABA nor block the reuptake of released GABA. They have no direct GABA.sub.A agonistic effect either. On the contrary, they react with specific binding sites which belong to a complex consisting of GABA receptors, various distinct modulatory receptors among others for benzodiazepines and a chlorine ion channel, and thus cause the GABA.sub.A receptor to undergo an allosteric change. This allosteric change influences the efficacy of GABA in promoting chloride channel opening.
However, such GABA.sub.A receptor modulators exhibit considerable side effects. Especially with the use of benzodiazepines, tolerance and dependency develop rapidly, and rebound insomnia, which will manifest itself by restlessness and somnipathy, emerges upon withdrawal.
Furthermore, the quality of sleep induced by said GABA.sub.A receptor modulators is unphysiological. REMS (=rapid eye movement sleep) as well as the deeper phases of nonREMS (slow-wave sleep) are disturbed.
For example, benzodiazepines and all other common hypnotics cause the following sleep profile.
1) they inhibit REMS PA0 2) they promote nonREMS PA0 3) they decrease delta activity (0.5-4 Hz) in the EEG within nonREMS by PA0 1) The total duration of nonREMS and REMS is increased after muscimol and THIP increases nonREMS, without decreasing REMS. PA0 2) Prolongation of nonREMS episodes as well as REMS episodes, which reflects an increase in sleep maintenance. PA0 3) The EEG-delta activity within nonREMS is enhanced; this is achieved by PA0 GABA.sub.A agonists which exert a direct effect on GABA.sub.A receptors, such as muscimol, thiomuscimol, THIP, thioTHIP, isoguvacine, PA0 GABA prodrugs, such as progabide, PA0 GABA uptake inhibitors, such as tiagabine and PA0 GABA transaminase inhibitors, such as vigabatrin.
a) reducing the rate of rise of delta activity at the beginning the nonREMS episodes, and PA1 b) reducing the maximum delta activity during nonREMS episodes. PA1 a) increasing the rise rate of delta activity at the beginning of each nonREMS episode, PA1 b) increasing the maximum delta activity during the nonREMS episodes, and PA1 c) prolonging the nonREMS episodes (see 2).
In one of two studies, Mendelson et al. (Life Sci 47, (1990) PL 99, 101; Life Sci 53 (1993) PL 81-87) found that muscimol, a GABA analogue and selective GABA.sub.A agonist, does cause a slight reduction of sleep latency but does not influence sleep as such. This finding resulted in the common opinion that non-benzodiazepoid GABA.sub.A agonists are devoid of any clinical beneficial effects on sleep disorders. Furthermore, it is generally accepted in the field that if a substance has a sedative side effect or causes a slight reduction in sleep latency, this will not justify its classification as a hypnotic.
In Pharmacol. Biochem. and Behaviour (1993), vol 45, 881-887, Suzuki et al investigated the effect of 3 mg/kg muscimol IP in different inbred strains of rats (Fischer 344, and Lewis) by measuring the loss and duration of the righting reflex. The authors of this document equate the duration of loss of the righting reflex to an hypnotic effect (sleep time). However, it is well established that the bahavioral parameter "righting reflex" bears no relationship with sleep. In the rat, very high doses of muscimol, such as 3 mg/kg, are known to evoke absence epilepsy. It is in fact highly likely tht the perceived sedation ("loss of righting reflex") represents a pathological state of an epileptiform nature (see "Hypersynchronisation and Sedation Produced by GABA-Transaminase Inhibitors and picrotoxin: Does GABA Participate in Sleep Control?", Waking and Sleeping (1979), 3: 245-254).
In U.S. Pat. No. 5,185,446 cycloalkylinidazo pyrimidine derivatives are disclosed which are described as being selective agonists, antagonists or inverse agonists for GABA.sub.A brain receptors and may be used in the diagnosis and treatment of anxiety, sleep and other disorders. All of these compounds are, however, allosteric GABA.sub.A -receptor modulators. In Pharmacol. Biochem. and Behaviour (1988), vol 29, 781-783, the hypnotic affects of the allosteric GABA.sub.A -receptor modulators are described.
The object underlying the present invention is to provide an effective hypnotic which has no significant side effects and causes a sleep profile essentially corresponding to physiological sleep.